Chiral guanidine catalysts

The chiral guanidine s role as a strong Brpnsted base for the reactions of protic substrates has been proposed. In 1999, Corey developed a C -symmetric chiral guanidine catalyst to promote the asymmetric Strecker reaction [117]. The addition of HCN to imines was promoted high yields and high enantioselectivities for both electron-withdrawing and electron-donating aromatic imines (Scheme 64). 

Ma and co-workers extended use of chiral guanidine catalysts to the addition of glycine derivatives to acrylates [121], Addition products were achieved in high yield with modest enantioselectivity (Scheme 67). The ferf-butyl glycinate benzophenone imines generally provided better enantiomeric ratios than the ethyl glycinate benzophenone imines. Based on this observation, the authors hypothesized that an imine-catalyst complex determines the stereochemical outcome of the product. 

Another structurally modified guanidine was reported by Ishikawa et al. as a chiral superbase for asymmetric silylation of secondary alcohols [122]. Soon after, Ishikawa discovered that the same catalyst promoted asymmetric Michael additions of glycine imines to acrylates [123]. The additions were promoted in good yield and great asymmetric induction under neat reaction conditions with guanidine catalyst 250 (Scheme 68). The authors deduced that the high conversion and selectivity were due to the relative configuration of the three chiral centers of the catalyst in... 

Terada and co-workers reported a novel guanidine catalyst with a chiral binaphthol backbone for the asymmetric addition of dicarbonyl compounds to nitro-olefins [126]. Substitution on the binaphthol backbone dramatically increased enantioselectivity. 

The axially chiral guanidine catalyst (155) (0.4-5 mol%) has been developed to facilitate the highly enantioselective Michael addition of 1,3-dicarbonyl compounds (g to a broad range of conjugated nitroalkenes (<98% ee).211... 

Scheme 7. Asymmetric Strecker synthesis with chiral guanidine catalyst 19 (Corey and Grogan).

There are reports that extend the nature of the catalyst beyond an oxazaborolidine framework. One such example made use of a chiral guanidine catalyst.11 Proline-derived 25 was converted to guanidine 26 in good yield. This species was capable of reducing ketones 27 to alcohols 28 by the addition of BH3-SMe2. 

With these results in hand, the Corey labs were able to utilize a readily available chiral C2-symmetical bifunctional guanidine catalyst 59.34 They rationalized the origin of the enantioselectivity to a pre-transition state assembly of the catalyst 59, the imine 60, and cyanide. Additionally, DFT modeling studies using the B3LYP method gave rise to two competitive pathways for the catalytic cycle.34b Concomitant hydrolysis of the nitrile and deprotection of the amine converted 61 to amino acids 62. 

An axially chiral and highly hindered binaphthyl-derived guanidine catalyst 18a with an internal guanidine unit (Figure 4.6) facilitates the highly enantioselective 1,4-addition... 

By installing aromatic substituents of suitable steric and electronic properties, this type of chiral guanidine catalyst could find numerous applications in asymmetric synthesis [67]. 

The beneficial effect of the presence of a guanidine moiety in the catalyst structure was showcased by Corey, who developed the C2-symmetric guanidine catalyst 157 (Equation 23) [113], This chiral guanidine furnishes enan-tioenriched a-aminonitriles (50-88% ees) from a variety of aromatic imines. The enantioselection was believed to arise from the bifunctional action of the guanidine catalyst as an activator of both the imine and the cyanide, as depicted in the proposed transition state structure 158. 

The wide applicability of the PK reaction is apparent in the synthesis of pyrroles, for example, 45, en route to novel chiral guanidine bases, levuglandin-derived pyrrole 46, lipoxygenase inhibitor precursors such as 47, pyrrole-containing zirconium complexesand iV-aminopyrroles 48 from 1,4-dicarbonyl compounds and hydrazine derivatives. The latter study also utilized Yb(OTf)3 and acetic acid as pyrrole-forming catalysts, in addition to pyridinium p-toluenesulfonate (PPTS). 

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